The major goal of this project is to discover restriction fragment length polymorphisms in the human which have high degrees of heterozygosity and which will therefore be extremely useful markers for mapping the human genome. These poly-morphisms will be mapped to specific chromosomal locations and probes which reveal them will be made available to collaborators for construction of linkage maps of specific chromosomal regions. Towards these ends, we plan to use cosmid libraries constructed from several rodent x human somatic cell hybrids containing single human chromosomes as sources of probes. specifically, we plan to obtain such sets of probes for chromosomes llq, 16q, and 17, such that each chromosomal region studied will be spanned by marker loci spaced at less than 20 cM intervals. Whole cosmids will be screened for their utility as probes to reveal polymorphisms by using a prehybridization method which allows large DNA segments to be used a sprobes vs. Southern blots despite the presence of repeated sequences in such probes. Cosmids which reveal multiple polymorphic loci when tested in this manner will be further investigated by subcloning to identify probes that reveal single polymorphic loci and by in situ hybridization to map the probes to specific chromosomal locations. Multiple polymorphisms that map within single cosmid inserts will be extremely useful markers for constructing linkage maps of human chromosomes. Such linkage maps will be efficient tools for assigning genes that cause serious genetic disease to specific regions of human chromosomes. In the long run information gained from using these polymorphisms may lead to isolation of defective genes and their normal counterparts, with important implications for treatment. Such information may also help to determine the genetic factors believed to contribute to the causation of numerous common diseases.